INSERM/UEVE U-861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, 91030 Evry cedex, France.
J Cell Sci. 2013 Apr 15;126(Pt 8):1763-72. doi: 10.1242/jcs.116285. Epub 2013 Feb 26.
Patients with myotonic dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among these are cognitive dysfunctions, the origin of which has remained elusive, partly because of the difficulty in accessing neural cells. Here, we have taken advantage of pluripotent stem cell lines derived from embryos identified during a pre-implantation genetic diagnosis for mutant-gene carriers, to produce early neuronal cells. Functional characterization of these cells revealed reduced proliferative capacity and increased autophagy linked to mTOR signaling pathway alterations. Interestingly, loss of function of MBNL1, an RNA-binding protein whose function is defective in DM1 patients, resulted in alteration of mTOR signaling, whereas gain-of-function experiments rescued the phenotype. Collectively, these results provide a mechanism by which DM1 mutation might affect a major signaling pathway and highlight the pertinence of using pluripotent stem cells to study neuronal defects.
肌强直性营养不良 1 型患者表现出多种影响许多不同器官的症状。其中包括认知功能障碍，其起源仍然难以捉摸，部分原因是难以获得神经细胞。在这里，我们利用从胚胎中衍生的多能干细胞系，这些胚胎是在携带突变基因的胚胎植入前遗传学诊断中确定的，从而产生早期神经元细胞。对这些细胞的功能特征分析表明，与 mTOR 信号通路改变相关的增殖能力降低和自噬增加。有趣的是，RNA 结合蛋白 MBNL1 的功能缺失会导致 DM1 患者的功能缺陷，其功能缺失会导致 mTOR 信号改变，而功能获得实验则挽救了表型。总的来说，这些结果提供了一种机制，说明 DM1 突变可能会影响主要的信号通路，并强调了使用多能干细胞研究神经元缺陷的相关性。
